Abstract
Women with mutations in the breast cancer susceptibility gene BRCA1 are predisposed to breast and ovarian cancers. Why the BRCA1 protein suppresses tumor development specifically in ovarian hormone-sensitive tissues remains unclear. We demonstrate that mammary glands of nulliparous Brca1/p53-deficient mice accumulate lateral branches and undergo extensive alveologenesis, a phenotype that occurs only during pregnancy in wild-type mice. Progesterone receptors, but not estrogen receptors, are overexpressed in the mutant mammary epithelial cells because of a defect in their degradation by the proteasome pathway. Treatment of Brca1/p53-deficient mice with the progesterone antagonist mifepristone (RU 486) prevented mammary tumorigenesis. These findings reveal a tissue-specific function for the BRCA1 protein and raise the possibility that antiprogesterone treatment may be useful for breast cancer prevention in individuals with BRCA1 mutations.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, U.S. Gov't, Non-P.H.S.
MeSH terms
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Animals
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Breast Neoplasms / genetics
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Breast Neoplasms / metabolism
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Cell Line, Tumor
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Cell Proliferation
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Epithelial Cells / cytology
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Epithelial Cells / metabolism
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Estradiol / pharmacology
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Estrous Cycle
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Female
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Genes, BRCA1*
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Genes, p53
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Hormone Antagonists / pharmacology*
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Hormone Antagonists / therapeutic use
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Humans
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Mammary Glands, Animal / cytology
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Mammary Glands, Animal / metabolism
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Mammary Neoplasms, Animal / genetics
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Mammary Neoplasms, Animal / prevention & control*
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Mice
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Mifepristone / pharmacology*
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Mifepristone / therapeutic use
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Mutation
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Phosphorylation
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Progesterone / antagonists & inhibitors*
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Progesterone / pharmacology
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Proteasome Endopeptidase Complex / metabolism
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RNA, Small Interfering
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Receptors, Estrogen / metabolism
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Receptors, Progesterone / genetics
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Receptors, Progesterone / metabolism*
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Ubiquitin / metabolism
Substances
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Hormone Antagonists
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RNA, Small Interfering
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Receptors, Estrogen
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Receptors, Progesterone
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Ubiquitin
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Mifepristone
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Progesterone
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Estradiol
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Proteasome Endopeptidase Complex